Polypeptide growth factor hormones utilize cell surface receptor tyrosine kinases (RTKs) and intracellular signaling pathways to direct a variety of cellular processes that contribute to development, including cellular proliferation, differentiation, migration, survival and fate determination. The aberrant activation of RTKs in cells can contribute to disease processes such as the genesis and progression of cancer. The mammalian ErbB receptor signaling network, consisting of four known RTKs and over a dozen different EGF-like growth factors, serves as a model for the generation of diversity and specificity in cellular signaling through RTKs. The hypothesis driving this proposal is that cells employ multiple modulation mechanisms that influence RTK response to stimulation by growth factors. Modulation of receptor activity in turn influences the selection of downstream signaling cascades that are utilized following ligand stimulation, and the intensity or duration in which these pathways are activated. The proposed studies seek to characterize novel mechanisms and proteins that modulate the response of ErbB family RTKs to their binding EGF-like growth factor ligands. The studies will focus on the modulation of the ErbB2/ErbB3 heterodimeric receptor species. The specific aims will be to: 1) understand the mechanisms by which ligand discrimination by the ErbB2/ErbB3 heterodimer leads to differential signaling; 2) understand the biochemical mechanisms underlying the potentiation of ErbB2/ErbB3 signaling by the cell surface glycoprotein ASGP2; and 3) understand the biochemical mechanisms underlying regulation of cellular ErbB3 receptor levels by the RING finger protein Nrdp1. [unreadable] [unreadable]